The insulin-like growth factor-I receptor (IGF-IR) mediates the growth and differentiation effects of the IGFs. Cancer cells overexpress IGF-IRs and this may impart to the cancer cells a growth potential. Recombinant human IGF-I (rhIGF-I) was administered, at varying doses, to nude mice that develop fibrosarcomas following injection of NIH-3T3 cells overexpressing IGF-I receptors. The administration of rhIGF-I at higher doses resulted in a shortened latency period, i.e., tumors appeared earlier than in vehicle-treated animals, and once the tumors appeared, they grew faster in the mice receiving the greater doses of rhIGF-I. The effect was also dependent on the level of IGF-IR expression, namely, the higher expression level of the receptor, the more responsive were the tumors. In studying the signaling pathways involved in IGF-I receptor- related tumor growth, we have identified a family of adapter proteins that may be involved in this process. CrkII and CrkL are SH2-SH3 domain-containing proteins. IGF-I receptor activation induces high-level tyrosine phosphorylation of both proteins and they both interact with insulin receptor substrate (IRS) molecules, whereas only CrkII interacts with the IGF-I receptor. Furthermore, the interaction of CrkII and CrkL with IRS-4 is different; Crk II interacts primarily via its SH2 domain, whereas CrkL requires both the SH2 domain and the N- terminal SH3 domain. This interaction with IRS-4 is tyrosine phosphorylation-dependent and deletion mutants demonstrated a central group of four residues (#700, 717, 743, 779) in IRS-4 that are involved in this interaction. When a fusion protein involving green fluorescent protein (GFP) and Crk proteins were expressed in cells in culture, followed by IGF-IR activation, GFP-CrkII was concentrated in the focal adhesion sites, whereas GFPCrkL remained diffusely expressed throughout the cell. IRS-4 overexpression in murine NIH-3T3 fibroblasts that express high levels of IGF-I receptor grow more rapidly than control cells in the presence of physiological concentrations of IGF-I, and overcome cell cycle arrest more readily. Thus, CrkII may play a role in the differentiated function following IGF-IR activation, whereas CrkL mediates a more oncogenic response to IGF-IR activation. Their differential interaction with the IGF-IR and IRS molecules, and presumably downstream signaling molecules may be one of the mechanisms whereby they mediate these different functions. MCF-7 breast cancer cells demonstrate cross talk between the estrogen receptor and the IGF-I receptor signaling cascade. There is synergy at the level of proliferation, signaling effects and cell cycle components. UV irradiation causes DNA damage, cell cycle arrest and apoptosis. These effects are rescued by IGF-I activation of the IGF-I receptor in NIH-3T3 cells. Thus the IGF-I receptor is essential for cellular proliferation and anti-apoptosis.